Dataset Information

Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.

ABSTRACT: OBJECTIVE:Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics. RESEARCH DESIGN AND METHODS:Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase-glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein. RESULTS:Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A, W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively; wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675 were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2 mmol/l, respectively; wild type = 5.0 mmol/l). CONCLUSIONS:These results confirm the potency of glucokinase as the pancreatic beta-cell glucose sensor, and they demonstrate that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to control than previously believed.

SUBMITTER: Sayed S

PROVIDER: S-EPMC2682682 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.

Sayed Samir S Langdon David R DR Odili Stella S Chen Pan P Buettger Carol C Schiffman Alisa B AB Suchi Mariko M Taub Rebecca R Grimsby Joseph J Matschinsky Franz M FM Stanley Charles A CA

Diabetes 20090331 6

<h4>Objective</h4>Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics.<h4>Research design and methods</h4>Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase-glucokinase fusion p ...[more]

PMID: 19336674

Similar Datasets

Project description:The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response.Article highlightsOur evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis.

Project description:BackgroundHyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively.ResultsAll patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3.ConclusionsWe demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Dataset Information

Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.

Publications

Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets